RESUMO
Objective: To investigate the functional lateralization of major Chinese language cortex in patients with cerebral arteriovenous malformation (AVM) in dominant hemispheric via functional magnetic resonance imaging (fMRI). Methods: Nine right-handed normal volunteers and fourteen patients with cerebral AVM in dominant hemisphere diagnosed in Beijing Tiantan Hospital between December 2017 and June 2018 were included. Three language tasks (semantic judgment, word reading, and listening comprehension) were applied to activate language areas. Lateralization index (LI) was used to show the dominant hemisphere. Results: In the control group, right-sided lateralization of BOLD signal activations was observed in 0/27 (0%) of the language tasks. While in the AVM patients, right-sided lateralization of BOLD signal activations was observed in 8/42 (19%) language tasks. The difference was statistically significant (χ(2)=5.73, P=0.019). Conclusions: The dominant hemisphere of different language tasks may be different in patients with cerebral lesions. Compared with normal controls, patients with cerebral AVM in dominant hemispheric are more likely to have right-sided lateralization of language cortex.
Assuntos
Idioma , Neurocirurgia , Mapeamento Encefálico , Córtex Cerebral , Lateralidade Funcional , Humanos , Imageamento por Ressonância MagnéticaRESUMO
AIM: To investigate apparent diffusion coefficient (ADC) as a prognostic indicator in primary central nervous system lymphoma (PCNSL) by analysing patient clinical characteristics and pretherapeutic diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Clinical characteristics and pretherapeutic DWI were studied retrospectively in 28 patients receiving high-dose methotrexate (HD-MTX)-based chemotherapy. Mean (ADCmean), 95th percentile (ADC95%), and 5th percentile (ADC5%) ADC values of the enhancing tumour volume were measured. The influence of prognostic parameters on progression-free survival (PFS) was investigated by log-rank test and Cox regression analysis. Correlations between the variables and PFS or the level of Ki-67 expression were analysed. ADC and clinical features were analysed using an independent sample t-test between the complete response (CRi) and partial response (PRi) groups after initial four cycles of chemotherapy. Receiver operating characteristic (ROC) curves were constructed using ADC parameters. RESULTS: Patients with CRi, lower Ki-67 level, higher Karnofsky performance status (KPS), ADC5%, or ADCmean showed better PFS. The level of Ki-67 expression and ADC5% were independent risk factors. There was a positive correlation between KPS, ADC5%, and PFS, and negative correlation between ADC5%, PFS, and the level of Ki-67 expression. There was a significant difference for PFS, KPS, ADCmean, and ADC5% between CRi and non-CRi; however, ADC5% outperformed ADCmean because the area under the ROC curve (AUC) using ADC5% (0.983) was higher than the AUC using ADCmean (0.822). CONCLUSION: ADC measurements, especially ADC5%, are useful predictors for PFS and response to HD-MTX in PCNSL.
Assuntos
Encéfalo/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética/métodos , Hospedeiro Imunocomprometido , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos , Neoplasias do Sistema Nervoso Central/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Linfoma não Hodgkin/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Interleukin-18 (IL-18), an important proinflammatory cytokine, has been reported to play a potential pathological role in rheumatoid arthritis (RA). Results from previous studies on the association between IL-18 polymorphisms and RA are conflicting. To clarify this, an updated meta-analysis of all available studies on IL-18 polymorphisms and RA was conducted. Eligible articles were identified by searching databases, including PubMed, Ovid, Cochrane Library, EMBASE, and China Knowledge Resource Integrated Database, for the period up to May 1, 2015. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were used to assess the strength of association in the homozygote, heterozygote, dominant, recessive, and additive models. The software STATA (Version 13.0) was used for statistical analysis. Finally, 14 articles were included in the present meta-analysis. The IL-18 -607C/A polymorphism showed pooled ORs and 95%CIs for the homozygote model (AA vs CC: OR = 0.598; 95%CI = 0.395-0.907), and the association between the IL-18 -137G/C polymorphism and RA showed pooled ORs and 95%CIs for the homozygote (CC vs GG: OR = 0.699; 95%CI = 0.364-1.342) and heterozygote (CG vs GG: OR = 0.924; 95%CI = 0.803-1.064) models. In summary, the current meta-analysis, which was based on the most current studies, showed that the -607A/C, -920C/T, and -105A/C polymorphisms in IL-18 were significantly associated with increased RA risk. However, the -137C/G polymorphism was not associated with RA risk under any genetic model. More evidence is needed to support or deny such a conclusion.
Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático/genética , Humanos , Razão de Chances , População Branca/genéticaAssuntos
COVID-19 , Epidemias , Neurocirurgia , Humanos , Procedimentos Neurocirúrgicos , SARS-CoV-2RESUMO
Somatostatin and its analog octreotide have been used successfully to treat postoperative chylothorax, and it has been shown that octreotide binds with high affinity to somatostatin receptor (SSTR) subtypes 2 and 5. Therefore, we investigated expression of SSTR2 and SSTR5 in the human thoracic duct by immunohistochemistry. Normal rat pancreas was used as a positive control for antibodies against SSTR2 and SSTR5, and Factor VIII-related antigen, SMA, actin, elastin, or collagen type II, III, IV or V antibodies were used to identify cell types and structures within the human thoracic duct. The antibodies against SSTR2 and SSTR5 worked well and yielded positive staining in control rat islets. In the human thoracic duct, SSTR2 was present in smooth muscle cells and some scattered structures which were stained by antibodies against Factor VIII-related antigen, SMA, actin, elastin or collagen type II, III, IV or V. SSTR5 was also present in smooth muscle cells. The presence of SSTR2 and SSTR5 in the human thoracic duct sheds light on the mechanism of somatostatin and octreotide use in the successful treatment of chylothorax and offers new molecular pathways to explore for potential future therapies.
Assuntos
Receptores de Somatostatina/biossíntese , Ducto Torácico/metabolismo , Animais , Humanos , Imuno-Histoquímica , Ratos , Ratos Wistar , Receptores de Somatostatina/análise , Ducto Torácico/químicaRESUMO
Cultured neonatal rat cardiac myocytes have been used extensively to study cellular and molecular mechanisms of cardiac hypertrophy. However, there are only a few studies in cultured mouse myocytes despite the increasing use of genetically engineered mouse models of cardiac hypertrophy. Therefore, we characterized hypertrophic responses in low-density, serum-free cultures of neonatal mouse cardiac myocytes and compared them with rat myocytes. In mouse myocyte cultures, triiodothyronine (T3), norepinephrine (NE) through a beta-adrenergic receptor, and leukemia inhibitory factor induced hypertrophy by a 20% to 30% increase in [(3)H]phenylalanine-labeled protein content. T3 and NE also increased alpha-myosin heavy chain (MyHC) mRNA and reduced beta-MyHC. In contrast, hypertrophic stimuli in rat myocytes, including alpha(1)-adrenergic agonists, endothelin-1, prostaglandin F(2alpha), interleukin 1beta, and phorbol 12-myristate 13-acetate (PMA), had no effect on mouse myocyte protein content. In further contrast with the rat, none of these agents increased atrial natriuretic factor or beta-MyHC mRNAs. Acute PMA signaling was intact by extracellular signal-regulated kinase (ERK1/2) and immediate-early gene (fos/jun) activation. Remarkably, mouse but not rat myocytes had hypertrophy in the absence of added growth factors, with increases in cell area, protein content, and the mRNAs for atrial natriuretic factor and beta-MyHC. We conclude that mouse myocytes have a unique autonomous hypertrophy. On this background, T3, NE, and leukemia inhibitory factor activate hypertrophy with different mRNA phenotypes, but certain Gq- and protein kinase C-coupled agonists do not.
Assuntos
Substâncias de Crescimento/farmacologia , Coração/efeitos dos fármacos , Interleucina-6 , Miocárdio/patologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Animais Recém-Nascidos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Células Cultivadas , Dinoprosta/farmacologia , Endotelina-1/farmacologia , Feto , Inibidores do Crescimento/farmacologia , Coração/embriologia , Hipertrofia , Interleucina-1/farmacologia , Fator Inibidor de Leucemia , Linfocinas/farmacologia , Camundongos , Microscopia de Contraste de Fase , Modelos Animais , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Miosinas/análise , Norepinefrina/farmacologia , Fenótipo , Fenilalanina/análise , Biossíntese de Proteínas , Proteínas/química , RNA Mensageiro/análise , Ratos , Acetato de Tetradecanoilforbol/farmacologia , Tri-Iodotironina/farmacologiaRESUMO
BACKGROUND: In the 7th tumor, node, metastasis (TNM) classification, T1 tumors with visceral pleural invasion (VPI) are upgraded to T2a. The objective of this study was to evaluate the prognostic impact of VPI among patients with NSCLC and to propose a method of incorporating VPI into T-status classification in future staging systems. METHODS: A systematic electronic search was conducted from each database's date of inception to October 2015. The included studies were selected according to predefined inclusion criteria. The hazard ratio (HR) was used as the outcome measure for data combining. RESULTS: A total of 22 studies, published from 2003 to 2015, were included in this meta-analysis. In the subgroup analysis, we identified that VPI was a poor prognostic factor for tumor size ≤2 cm (2.34 [95% confidence interval (CI) 1.55-3.54; P < 0.0001]), 2-3 cm (1.81 [95% CI 1.56-2.10; P < 0.0001]), 3-5 cm (1.61 [95% CI 1.38-1.87; P < 0.0001]) and 5-7 cm (1.50 [95% CI 1.24-1.82; P < 0.0001]). In addition, we also found that there were no significant differences for the following comparisons of OS: tumor size ≤2 cm with VPI versus 3-5 cm without VPI (1.04 [95% CI 0.83-1.31; P = 0.34]); 2-3 cm with VPI versus 3-5 cm without VPI (1.04 [95% CI 0.96-1.13; P = 0.30]); 3-5 cm with VPI versus 5-7 cm without VPI (0.95 [95% CI 0.78-1.17; P = 0.66]); and 5-7 cm with VPI versus T3 status (1.03 [95% CI 0.93-1.14; P = 0.57]). CONCLUSIONS: In addition to the current TNM classification recommendations, consideration should be given to classifying the T2a tumors with VPI as T2b and classifying T2b with VPI as T3 in the next edition of the TNM Classification for Lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Pleura/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Invasividade Neoplásica , Prognóstico , Viés de PublicaçãoRESUMO
This study was conducted to investigate the protective effects of sodium p-aminosalicylic acid (PAS-Na) on learning and memory via increasing the number of basal forebrain choline acetyltransferase (ChAT) neurons in manganese (Mn)-exposed rats. Male Sprague Dawley rats were divided into following groups: the normal control I, II, and III groups, the model I, II, and III groups, low- and high-dose PAS-Na treatment (L- and H-PAS) group, PAS-Na prevention (PAS-P) group, and PAS-Na treatment (PAS-T) group. The model I, II, and III groups, L- and H-PAS, and PAS-T groups received intraperitoneal (i.p.) injection of 15 mg/kg manganese chloride tetrahydrate (MnCl2·4H2O) for 3 or 12 weeks, while the normal control I, II, and III groups received i.p. injection of an equal volume of saline; L- and H-PAS and PAS-T groups received back subcutaneous (s.c.) injection of PAS-Na (100 and 200 mg/kg) for the next 5 or 6 weeks, whereas model I and II group received back s.c. injection of an equal volume of saline. However, PAS-P group received back s.c. injection of 200 mg/kg PAS-Na + i.p. injection of 15 mg/kg MnCl2·4H2O for 12 weeks. Mn exposure significantly reduced the ability of spatial learning and memory capability, while PAS-Na prevention recovered it. Mn decreased the number of ChAT-positive neurons in vertical limb nucleus of the basal forebrain diagonal band/horizontal limb nucleus of the basal forebrain diagonal band and ChAT protein activity and treatment or prevention with PAS-Na restored those comparable with control. In brief, our results showed that PAS-Na may have protective effects on learning and memory against Mn via increasing the number of ChAT-positive neurons and activity of ChAT protein.
Assuntos
Ácido Aminossalicílico/farmacologia , Colina O-Acetiltransferase/metabolismo , Transtornos Cognitivos/enzimologia , Intoxicação por Manganês/enzimologia , Fármacos Neuroprotetores/farmacologia , Ácido Aminossalicílico/uso terapêutico , Animais , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/enzimologia , Transtornos Cognitivos/tratamento farmacológico , Aprendizagem/efeitos dos fármacos , Masculino , Intoxicação por Manganês/tratamento farmacológico , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Sprague-DawleyRESUMO
1. This study was done to characterize the functional role of alpha 1D-adrenoceptors in rat myocardium, aorta, spleen, vas deferens and prostate by use of the selective antagonist BMY 7378. 2. BMY 7378 inhibited [3H]-prazosin binding to aortic membranes with a potency (pKi 9.8 +/- 0.40) approximately 100 fold higher than in right ventricular membranes (pKi 7.47 +/- 0.11) and approximately 1,000 fold higher than that in plasma membranes of the prostate (pKi 6.62 +/- 0.39), vas deferens (pKi 6.67 +/- 0.15), salivary gland (pKi 6.46 +/- 0.38) and liver (6.58 +/- 0.06). 3. BMY 7378 antagonized the positive inotropic effects of phenylephrine (in the presence of 1 microM propranolol) on right ventricles (pA2 7.0 +/- 0.11), left atria (pKB 7.04 +/- 0.18) and papillary muscles (pKB 6.9 +/- 0.1) and inhibited phenylephrine-induced increase in inositol phosphates. 4. BMY 7378 was approximately 100 fold more potent as an antagonist of phenylephrine on aortic strips (pA2 9.0 +/- 0.13) than on vas deferens (pKB 7.17 +/- 0.08) and spleen (pKB 7.16 +/- 0.21); it was ineffective on the prostate. 5. Chloroethylclonidine suppressed the maximal effects of phenylephrine on spleen; 5-methylurapidil antagonized the effects of phenylephrine on aortic strips (pA2 7.98 +/- 0.08), vas deferens (pKB 8.89 +/- 0.07) and prostate (pKB 8.85 +/- 0.21). 6. BMY 7378 caused a dose (0.1-100 nmol kg-1)-dependent decrease in mean blood pressure of urethane-anaesthetized rats and its hypotensive efficacy was equal to that of hexamethonium. 7. The data suggest that alpha 1D-adrenoceptors play a significant role in rat aorta, a minor role in the heart, vas deferens and spleen and virtually no role in the prostate.
Assuntos
Aorta Torácica/ultraestrutura , Miocárdio/ultraestrutura , Receptores Adrenérgicos alfa 1/classificação , Receptores Adrenérgicos alfa 1/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/antagonistas & inibidores , Cardiotônicos/farmacologia , Técnicas In Vitro , Fígado/ultraestrutura , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Fenilefrina/antagonistas & inibidores , Fenilefrina/farmacologia , Piperazinas/farmacologia , Prazosina/metabolismo , Prazosina/farmacologia , Próstata/efeitos dos fármacos , Próstata/ultraestrutura , Ratos , Ratos Sprague-Dawley , Glândulas Salivares/ultraestrutura , Baço/efeitos dos fármacos , Baço/ultraestrutura , Trítio , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/ultraestruturaRESUMO
1. Negative inotropic effects of several beta-adrenoceptor (betaAR) antagonists on electrically-stimulated right atria, left atria, right ventricles and left ventricular papillary muscles from reserpine-treated rats were used as a measure of their inverse agonist activities. 2. Beta1AR antagonists acebutolol, atenolol and metoprolol, beta2AR antagonist ICI-181,551 and nonselective betaAR antagonists alprenolol, nadolol, propranolol and timolol produced negative inotropic effects, which were most marked on the right atria. 3. The nonselective betaAR antagonist pindolol did not exhibit inverse agonist activity but inhibited the negative inotropic activities of ICI-118,551, atenolol and propranolol. 4. The negative inotropic effects of lidocaine, nifedipine and pentobarbitone were similar on all the four myocardial preparations. 5. The positive inotropic efficacy of salbutamol on right and left atria but not on right ventricles and papillary muscles was comparable to that of isoprenaline. The antagonist activity of ICI-118,551 against isoprenaline was greater on right atria than on other cardiac regions. 6. Beta1AR proteins were expressed in all regions of the heart but of beta2AR were primarily localized in the right atrium. 7. It is concluded that beta2AR play a greater role in right atria than in other cardiac regions and almost all betaAR antagonists behave as inverse agonists.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Contração Miocárdica/efeitos dos fármacos , Propanolaminas/farmacologia , Albuterol/farmacologia , Animais , Western Blotting , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Pindolol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/fisiologia , Receptores Adrenérgicos beta 2/fisiologiaRESUMO
BACKGROUND: Esophagogastrostomy for oesophageal cancer is the standard surgical treatment. However, traditional techniques have been associated with high frequency of anastomotic complications. The purpose of this study is to clarify the superiority of the oesophageal flap valvuloplasty and wrapping suturing technique in preventing postoperative complications after oesophagectomy for oesophageal cancer. METHODS: A prospective, randomised study was performed on 394 patients treated for esophageal cancer between January 2006 and December 2010. The trial registry number is ChiCTR-TRC-13003817 in the Chinese Clinical Trial Registry. RESULTS: Anastomotic leaks occurred in four patients in group A (2.1%) and in twelve patients in group B (6.2%) with statistically significant (P = 0.038). During the evaluation of benign stricture seven patients were excluded for hospital mortality. Thirty three patients in group A (6.9%) and 25 patients in group B (13.2%) occurred anastomotic stricture respectively (P = 0.044). Furthermore, reflux oesophagitis and Barrett's epithelium were found in 105 patients (55.3%) of group B, and 54 (28.7%) patients in group A (P < 0.001). CONCLUSION: The oesophageal flap valvuloplasty and wrapping suturing technique decreased anastomotic leakage incidence and stricture rate thereby decreasing the morbidity and mortality. This procedure also prevented the occurrence of gastroesophageal reflux after esophagectomy.
Assuntos
Adenocarcinoma/cirurgia , Fístula Anastomótica/prevenção & controle , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Esôfago/cirurgia , Refluxo Gastroesofágico/prevenção & controle , Estômago/cirurgia , Técnicas de Sutura , Adulto , Idoso , Anastomose Cirúrgica/métodos , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Retalhos Cirúrgicos , Resultado do TratamentoRESUMO
This study investigated the role of alpha 1D-adrenoceptors (ARs) in the inotropic responses of neonatal (7-day-old) rat myocardium by using the relatively selective antagonist BMY 7378. The positive inotropic effects of phenylephrine on right ventricular strips of neonatal rats were not inhibited by BMY 7378 up to a concentration of 300 nM but potently antagonized by the alpha 1AAR antagonist 5-methylurapidil (5-MU) (pKB, 8.73 +/- 0.12; n = 6). BMY 7378 was approximately 1,000-fold less potent (pKi, 6.63 +/- 0.7; n = 5) in inhibiting the binding of [3H]prazosin to right ventricular membrane preparations of neonatal rats than was 5-MU (pKi, 9.04 +/- 0.54; n = 5). Neonatal rat cerebral cortex and adult rat aorta were used as additional controls. BMY 7378 was a weak inhibitor of [3H]prazosin binding to neonatal cortex (pKi, 6.8 +/- 0.04; n = 3) but highly potent in inhibiting the binding to adult rat aortic membrane preparations (pKi for high-affinity binding, 9.70 +/- 0.30; n = 4); BMY 7378 potently antagonized the effects of phenyleprine on adult rat aortic strips (pKB, 9.05 +/- 0.11; n = 5). It is concluded that alpha 1DARs do not play a significant role in alpha 1AR-mediated inotropic responses of neonatal rat myocardium.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacologia , Miocárdio/metabolismo , Piperazinas/farmacologia , Função Ventricular , Animais , Animais Recém-Nascidos , Aorta/metabolismo , Membrana Celular/metabolismo , Córtex Cerebral/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Fenilefrina/farmacologia , Prazosina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
alpha-Adrenoceptors (alpha1AR) are G protein-coupled receptors and include alpha1A, alpha1B, and alpha1D subtypes corresponding to cloned alpha1a, alpha1b, and alpha1d, respectively. alpha1AR mediate several cardiovascular actions of sympathomimetic amines such as vasoconstriction and cardiac inotropy, hypertrophy, metabolism, and remodeling. alpha1AR subtypes are products of separate genes and differ in structure, G protein-coupling, tissue distribution, signaling, regulation, and functions. Both alpha(1A)AR and alpha(1B)AR mediate positive inotropic responses. On the other hand, cardiac hypertrophy is primarily mediated by alpha(1A)AR. The only demonstrated major function of alpha(1D)AR is vasoconstriction. alpha1AR are coupled to phospholipase C, phospholipase D, and phospholipase A2; they increase intracellular Ca2+ and myofibrillar sensitivity to Ca2+ and cause translocation of specific phosphokinase C isoforms to the particulate fraction. Cardiac hypertrophic responses to alpha1AR agonists might involve activation of phosphokinase C and mitogen-activated protein kinase via Gq x alpha1AR subtypes might interact with each other and with other receptors and signaling mechanisms.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/fisiologia , Animais , Humanos , Receptores Adrenérgicos alfa 1/efeitos dos fármacosRESUMO
We investigated the role of protein kinase C (PKC) in alpha 1-adrenoceptor (alpha 1-AR)-mediated positive inotropic responses of neonatal rat myocardium. Bisindolylmaleimide (BIM), an inhibitor of all PKC isoforms, reduced the positive inotropic responses to phenylephrine and methoxamine but not to isoproterenol. The positive inotropic effect of phenylephrine was not attenuated by Gö-6976, a selective inhibitor of Ca(2+)-dependent isoforms; it was potentiated by the 1,2-diacylglycerol kinase inhibitor R-59949. Phorbol 12,13-dibutyrate, an activator of both Ca(2+)-dependent and-independent PKC isoforms, as well as thymeleatoxin, a selective activator of Ca(2+)-dependent PKC isoforms, inhibited myocardial contractions, which were prevented by BIM and Gö-6976. BIM inhibited the phenylephrine-induced increase in particulate PKC activity but not the increase in phosphatidylinositide turnover. Phenylephrine induced translocation of only Ca(2+)-independent PKC-epsilon and -delta. These results suggest that activation of Ca(2+)-independent PKC isoforms by alpha 1-AR agonists plays a key role in alpha 1-AR-mediated positive inotropic effect on neonatal myocardium.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Isoenzimas/metabolismo , Metoxamina/farmacologia , Contração Miocárdica/fisiologia , Fenilefrina/farmacologia , Proteína Quinase C/metabolismo , Receptores Adrenérgicos alfa 1/fisiologia , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Carbazóis/farmacologia , Diacilglicerol Quinase , Estimulação Elétrica , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Ventrículos do Coração , Técnicas In Vitro , Indóis/farmacologia , Fosfatos de Inositol/metabolismo , Isoproterenol/farmacologia , Maleimidas/farmacologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Dibutirato de 12,13-Forbol/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Piperidinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Quinazolinas/farmacologia , Quinazolinonas , Ratos , Ratos Sprague-DawleyRESUMO
The present study was done to determine possible ontogenic differences in the functions of rat myocardial alpha1, adrenoceptor (alpha1 AR) subtypes in view of reported greater inotropic responses of myocardium of neonatal than of adult rats to alpha1, AR agonists. Methoxamine, phenylephrine and norepinephrine were used as alpha1 AR agonists. Phenylephrine and norepinephrine were used in the presence of 3 microM propranolol. It was found that the ratios of chloroethylclonidine (CEC)-insensitive alpha1 AR subtype (alpha1A AR) to CES-sensitive alpha, AR subtype (alpha1B AR) were approximately 50:50 in neonatal (1 week old) and 20:80 in adult rat ventricles. alpha1A AR selective antagonists WB 4101 and 5-methylurapidil+ (5-MU) inhibited the inotropic effects of alpha1, AR agonists both on neonatal and on adult rat ventricles; in contrast, selective inactivation of alpha1B AR by CEC inhibited the inotropic effects of alpha1 AR agonists only on ventricles from adult but not from neonatal animals. WB 4101 inhibited methoxamine-induced increases in inositol phosphates by ventricular slices from both adult and neonatal rats; in contrast, CEC inhibited these effects of methoxamine only in tissues from adult but not in tissues from neonatal animals. In conclusion, this study, to our knowledge, demonstrates for the first time that the effects of alpha AR agonists on right ventricular contractions and phosphoinositol turnover are mediated primarily by alpha 1A AR subtype in the neonatal and by both alpha1A AR and alpha1B AR subtypes in the adult rat.
Assuntos
Coração/efeitos dos fármacos , Miocárdio/metabolismo , Receptores Adrenérgicos alfa 1/fisiologia , Animais , Relação Dose-Resposta a Droga , Metoxamina/farmacologia , Norepinefrina/farmacologia , Fenilefrina/farmacologia , Prazosina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/efeitos dos fármacosRESUMO
This study investigated the mechanism of the positive inotropic effects of class 1 antiarrhythmic agents using electrically stimulated right atria (sinoatrial node excised), left atria and right ventricles of rats. Quinidine, disopyramide and procainamide produced concentration-dependent positive inotropic effects on right and left atria; effects on the right atria were greater than on left atria. At concentration producing positive inotropic effects on atria, the contractions of right ventricles were slightly increased by quinidine, unaffected by disopyramide and decreased by procainamide. The positive inotropic effects of quinidine were inhibited by propranolol, reserpine and mecamylamine but not by cocaine, hexamethonium and d-tubocurarine; propranolol also antagonized the positive inotropic effects of disopyramide and procainamide. Bupivacaine, which like quinidine blocks transient outward potassium current, slightly increased the contractions of right atria but not of left atria and ventricles. The atrium-specific positive inotropic effects of quinidine were mimicked by atropine, pirenzepine and dimethylphenylpiperazinium but not by nicotine, cytisine and butyrylcholine; the effects of atropine, dimethylphenylpiperazinium and pirenzepine were also blocked by propranolol. Quinidine increased the release of norepinephrine from atria but not from the ventricles; this release was greater from the right than from the left atria. It is concluded that quinidine- and atropine-like agents exert atrium-specific positive inotropic effects by blocking muscarinic receptors and permitting a dominance of acetylcholine effects via a release of norepinephrine from sympathetic nerve terminals.
Assuntos
Antiarrítmicos/farmacologia , Atropina/farmacologia , Contração Miocárdica/efeitos dos fármacos , Quinidina/farmacologia , Animais , Bupivacaína/farmacologia , Catecolaminas/metabolismo , Iodeto de Dimetilfenilpiperazina/farmacologia , Disopiramida/farmacologia , Átrios do Coração/efeitos dos fármacos , Isoproterenol/farmacologia , Masculino , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/fisiologia , Estimulação QuímicaRESUMO
We investigated if the refractoriness to the tocolytic effects of atrial natriuretic factor (ANF) during rat pregnancy is due to a downregulation of one or both guanylyl cyclase (GC)-coupled GC-A and GC-B ANF receptors; lungs were used as controls. Uteri and lungs of virgin, pregnant (days 7, 16, and 21), and day 2 postpartum rats expressed mRNAs for GC-A and GC-B as well as GC-uncoupled ANF-C receptors. GC-B receptor protein was more abundant than GC-A in uteri; the reverse was the case in lungs. Pregnancy decreased uterine mRNAs and proteins for GC-A and GC-B receptors as well as the effects of ANF and C-type natriuretic peptide (CNP) on uterine GC activity; lung ANF receptors and effects of ANF and CNP on lung GC activity were not modulated by pregnancy. It is concluded that pregnancy induces organ-specific modulation of ANF receptors and a downregulation of ANF-GC receptors would minimize interference with uterine motility during pregnancy.
Assuntos
Regulação para Baixo , Guanilato Ciclase/metabolismo , Pulmão/metabolismo , Prenhez/fisiologia , Receptores do Fator Natriurético Atrial/biossíntese , Útero/metabolismo , Animais , Fator Natriurético Atrial/farmacologia , Feminino , Masculino , Peptídeo Natriurético Tipo C , Gravidez , Proteínas/farmacologia , Ratos , Ratos Sprague-Dawley , Útero/efeitos dos fármacosRESUMO
Distribution of alpha(1)-adrenoceptor (alpha(1)AR) subtype (alpha(1A), alpha(1B), alpha(1D)) proteins in brain, heart, kidney, and liver of 1-week-old rats and in brain, heart, aorta, kidney, liver, vas deferens, prostate, and adrenal glands of adult rats was investigated by Western analysis, using receptor subtype specific polyclonal antibodies. High levels of immunoreactive alpha(1A)AR and alpha(1D)AR in brain and heart and of alpha(1B)AR in liver and heart of neonatal rats were detected. In adult rat tissues, the abundance of alpha(1A)AR protein was most marked in the brain, intermediate in heart, aorta, liver, vas deferens, and adrenals, and minimal in the kidney and prostate; relative to other tissues, the expression of alpha(1B)AR was higher in brain and heart and that of alpha(1D)AR in brain. All the three receptor subtypes increased with age in the brain cortex, whereas the abundance of alpha(1B)AR increased in the heart but decreased in the liver; alpha(1A)AR and alpha(1D)AR in liver, kidney, and heart were not affected by age. It is concluded that alpha(1)AR subtypes are widely expressed in different neonatal and adult rat tissues.